Government Relations & Policy Advocacy – Focus on Regulationhttps://www.hlregulation.com
Thu, 23 May 2019 23:42:36 +0000en-UShourly1https://wordpress.org/?v=4.9.10FDA guidance may ease path to biosimilar interchangeabilityhttps://www.hlregulation.com/2019/05/15/fda-guidance-may-ease-path-biosimilar-interchangeability/
Wed, 15 May 2019 22:40:32 +0000https://www.hlregulation.com/?p=11183On Friday, FDA published the final guidance, “Considerations in Demonstrating Interchangeability With a Reference Product,” which is intended to assist sponsors in demonstrating that a biosimilar product is interchangeable with a reference product. Even as some of the details remain to be hashed out, the guidance makes clear FDA’s desire to minimize the burdens of

]]>On Friday, FDA published the final guidance, “Considerations in Demonstrating Interchangeability With a Reference Product,” which is intended to assist sponsors in demonstrating that a biosimilar product is interchangeable with a reference product. Even as some of the details remain to be hashed out, the guidance makes clear FDA’s desire to minimize the burdens of obtaining a determination of interchangeability. The guidance summarizes the important scientific considerations for demonstrating interchangeability, including:

The data and information recommended to support a demonstration of interchangeability

Considerations for the design and analysis of a switching study or studies to support a demonstration of interchangeability

Considerations regarding the comparator product in a switching study or studies

The finalized version of the guidance maintains the principles and structure of the January 2017 draft version, which we discussed here. In general, it provides a flexible framework that emphasizes the “totality of the evidence” in a given case, with interchangeability determinations guided by product-specific assessment of immunogenicity risks and other factors.

Switching studies

The final guidance makes clear that, for products that will be used more than once in a given patient, FDA generally will expect sponsors to conduct “switching studies,” i.e., clinical trials that switch patients back and forth between the reference biologic and the biosimilar. If the switching study is intended to support a finding of interchangeability for an already-licensed biosimilar, FDA says, existing postmarketing data for the biosimilar might be harnessed to support the interchangeability finding. If a interchangeability finding is requested with an initial biosimilar application, the agency contemplates that the switching study could be “integrated” with the study required to show biosimilarity. The final guidance also confirms that the primary endpoints for switching studies can be pharmacokinetic (PK) and/or pharmacodynamics (PD) markets, not clinical efficacy. Additionally, FDA generally will permit extrapolation of data from one condition of use to another.

The final guidance contains two notable changes from the draft: it permits switching studies to use non-U.S. versions of the reference product, and suggests flexibility regarding healthy subjects being used in switching studies. Additionally, the final guidance is much more general about the requirement to demonstrate interchangeability regarding the biosimilar and reference products’ presentation. In cutting much of the detail in the draft guidance, FDA has said it will issue a separate guidance to “provide more detailed recommendations on the data and information recommended to support the proposed interchangeable product’s presentation, container closure systems, and delivery device constituent parts and related issues.”

Encouraging interchangeable biosimilars

In a statement announcing the guidance, Acting FDA Commissioner Ned Sharpless emphasized FDA’s commitment to advancing the regulatory approval pathway for biosimilar and interchangeable products, citing agency plans to provide greater clarity for applicants and other stakeholders that are outlined in its Biosimilars Action Plan, which we discussed here. By way of example, Dr. Sharpless noted that there are no approved generic insulin products that can be substituted for branded products, but suggested that could change after March 2020, when insulin products approved under NDAs will be deemed to be licensed via BLAs, which may lead to biosimilar and interchangeable biosimilar insulin products. This guidance will help that happen, Dr. Sharpless said.

If you have any questions about the final guidance or may be interested in applying for an interchangeability designation, please contact any of the authors of this blog or the Hogan Lovells lawyer with whom you regularly work.

]]>FDA Doubles Down on MUsT Studies for Sunscreens and Issues Final Guidance on Absorption Studies that Will Likely Be Needed for Continued Marketinghttps://www.hlregulation.com/2019/05/14/fda-doubles-down-must-studies-for-sunscreens-issues-final-guidance-absorption-studies/
Tue, 14 May 2019 19:58:12 +0000https://www.hlregulation.com/?p=11171On May 10, 2019, FDA published a notice of availability for a final guidance document on Maximal Usage Trials (MUsT studies) for topically applied active ingredients being considered for OTC drug monographs, including sunscreens. As FDA has previously explained, the guidance states that MUsT studies can identify the potential for the systemic exposure for a

]]>On May 10, 2019, FDA published a notice of availability for a final guidance document on Maximal Usage Trials (MUsT studies) for topically applied active ingredients being considered for OTC drug monographs, including sunscreens. As FDA has previously explained, the guidance states that MUsT studies can identify the potential for the systemic exposure for a topically-applied active ingredient. FDA believes that this information is necessary to determine whether additional safety studies are needed to support a finding that the ingredient is generally recognized as safe and effective (GRASE) for its intended use.

FDA’s reliance on MUsT studies has been a subject of controversy with the sunscreens industry. Industry has argued that MUsT studies are unreasonably expensive and sunscreen products have been marketed in the U.S. and around the world for decades without adverse events or data identifying safety concerns related to absorption. To support an OTC drug monograph, FDA has said that a MUsT study should evaluate the ingredient in a range of formulations, which further adds to the cost and time needed for such a study.

FDA: Absorption Is Not Just a Theoretical Concern

However, just a few days before the issuance of the MUsT guidance, on May 6, 2019, FDA released a statement reaffirming the agency’s reliance on MUsT studies for evaluating sunscreens. The FDA statement highlights an FDA-funded study published on the same day in the Journal of the American Medical Association (JAMA), evaluating the absorption of four sunscreen ingredients: avobenzone, oxybenzone, octocrylene, and ecamsule. The FDA statement was intended to emphasize that “that absorption of sunscreens is not just a theoretical concern.” According to the JAMA article, all four ingredients were absorbed such that systemic concentrations greater than 0.5 ng/mL (nanograms per milliliter) were reached after four applications on day 1. FDA’s statement reflects the agency’s position that sunscreen active ingredients absorbed above this threshold “would generally need to undergo further testing to help determine if they increase the risk for cancer, birth defects or other adverse effects.”

Private Meetings in Support of Developing MusT Studies

Highlights of the MUsT guidance include the following:

FDA encourages MUsT study sponsors to seek FDA’s advice before initiating a MUsT study to support OTC monograph status for a particular ingredient.

Although the results of MUsT study would ultimately need to be included in the public docket to support inclusion of a particular active ingredient in the OTC drug monograph, FDA is willing to hold private meetings with sponsors to discuss MUsT protocol details that are not yet part of the public record. This would give sponsors the opportunity to privately discuss and receive input from FDA about their preliminary plans to generate MUsT data.

However, minutes from the private meetings, including a summary of general concepts discussed, would subsequently be submitted to the public docket. But information that sponsors would not routinely publicly disclose, such as chemistry data and detailed protocols, would not be disclosed to the extent that they constitute confidential commercial or trade secret information.

Rulemaking Deferral Requests

The issuance of the guidance follows FDA’s decision published on April 18, 2019, to extend both the comment period on the proposed sunscreens rule and the period to request a rulemaking deferral for certain active ingredients. FDA granted a 30-day extension, until June 27, 2019. The extension is of particular importance for the manufacturers of the 12 sunscreen ingredients that were identified in the proposed rule as requiring additional data and information, in particular relating to absorption, to determine whether the ingredients could be established as GRASE. To provide the absorption data, the proposed rule stated that FDA expects that data from a MUsT study “will be needed to support an adequate assessment of safety for most sunscreen active ingredients.” 84 FR 6204, 6213 (Feb. 26, 2019).

FDA invited requests for the agency to defer rulemaking for certain ingredients, to allow for the submission of the necessary data. But the language of the proposed rule appeared to signal that FDA would not grant such deferrals unless it appeared that the “sum of the data … would be adequate” to provide all the data necessary to establish GRASE. 84 FR 6204 at 6249.

We believe that FDA is not likely to grant a deferral request for a sunscreen ingredient without a commitment to conduct a MUsT study. And additional safety studies are likely to be expected for at least the four ingredients identified in the JAMA article as exceeding FDA’s absorption threshold. However, FDA’s May 6 statement described above adopted a softer tone for sunscreen manufacturers willing to commit to MUsT studies, stating that “we understand that manufacturers may need additional time to generate new data and information” and will consider deferral requests for this purpose.

In a previous post, we explained that FDA is facing a statutory deadline to finalize the sunscreens monograph by November 26, 2019. Now that FDA has granted an extension for comments, it will be even more difficult for FDA to meet with this deadline. It is possible that FDA will miss the deadline and take its chances on being sued. But it is also possible that FDA will grant deferrals for any of the 12 ingredients for which there is a credible commitment to conduct the necessary MUsT and related studies. The studies could be conducted over an extended period of time, which would allow for continued marketing during the interim period, as long as FDA continues to renew the deferrals. Taking a generous approach to deferrals could ease the path for FDA to finalize the remainder of the rule in accordance with the statutory deadline.

If you have any questions about the MUsT guidance or may be interested in submitting a comment to the proposed rule or deferral request, please contact any of the authors of this blog or the Hogan Lovells lawyer with whom you regularly work.

]]>FDA publishes final guidance on ANDA/505(b)(2) NDA pathwayshttps://www.hlregulation.com/2019/05/10/fda-publishes-final-guidance-anda-505b2-nda-pathways/
Fri, 10 May 2019 21:40:51 +0000https://www.hlregulation.com/?p=11162On Thursday, FDA published the final guidance document, “Determining Whether to Submit an ANDA or a 505(b)(2) Application” that contains minor revisions to the October 2017 draft guidance. The final guidance contains no significant substantive changes to the draft version, but here are a few interesting tidbits: FDA will respond to comments seeking clarification on

]]>On Thursday, FDA published the final guidance document, “Determining Whether to Submit an ANDA or a 505(b)(2) Application” that contains minor revisions to the October 2017 draft guidance. The final guidance contains no significant substantive changes to the draft version, but here are a few interesting tidbits:

FDA will respond to comments seeking clarification on the process for obtaining therapeutic equivalence evaluations in a forthcoming guidance document.

FDA clarified that petitioned ANDAs are expected to have the same therapeutic effect as the reference listed drug.

Revisions to the discussion about what kind of information may be submitted in an ANDA seem to emphasize FDA’s “significant flexibility” on this issue.

As always, the devil is in the details. Much policy will be developed in the context of individual applications. For more information on how to strategically approach drug approval pathways (yours or a competitor’s), please contact any of the authors of this alert or the Hogan Lovells lawyer with whom you regularly work.

]]>On April 23, FDA issued draft guidance entitled “Initiation of Voluntary Recalls Under 21 CFR Part 7, Subpart C,” which aims to clarify how firms in a product distribution chain should prepare to facilitate timely initiation of a voluntary recall, respond to an indication of a problem with a distributed product, and initiate a voluntary recall. Overall, FDA emphasizes the importance of pharmaceutical, biotechnology, medical device, food, tobacco, and animal products firms having made plans in advance of a recall so that they are prepared, should one become necessary.

How to be “Recall Ready”

In order to facilitate timely initiation of a voluntary recall, the draft guidance recommends firms make the following preparations:

Designate specific employees with recall-related responsibilities who possess the authority to take the steps needed to implement a product recall when necessary.

Train personnel on recall-related responsibilities, and consider additional preparatory steps such as mock recalls and establishing metrics appropriate to a recall plan.

Create a recall communications plan that identifies specific points-of-contact, and that contains draft templates that help the firm issue recall communications promptly.

Identify possible recall-associated reporting requirements, for circumstances when a significant problem with a distributed product may trigger a requirement to make a separate report to FDA, g., a report to the Reportable Food Registry or reports under 21 CFR 806 for medical devices.

Ensure adequate product coding to make possible positive lot identification and to facilitate the effective recall of all violative lots.

Maintain product distribution records for a period of time that exceeds the shelf life and expected use of the product and is at least the length of time specified in other applicable regulations concerning records retention. The records should contain enough detail to identify the consignees that actually received the recalled product and must conform to any applicable requirements.

The draft guidance further advises a firm to maintain written recall initiation procedures that assign responsibility and describe the steps to perform all actions related to initiating a recall, as appropriate to the specific products and business model of the firm or facility. These procedures should include actions such as (1) ceasing distribution, shipment or sales of affected product; (2) developing a recall strategy; (3) notifying direct consignees; and (4) when appropriate, notifying the public of the recall.

Steps for responding to an indication of a problem

The draft guidance outlines specific steps a firm should take if there is an indication of a problem with a distributed product:

Identify the problem using indicators such as an internal report of a product specification deviation or out-of-specification testing results for a product.

Promptly investigate the problem to ensure that potential risks are consistently assessed and investigated for products potentially affected.

Make decisions about whether a recall is necessary, and if so, about the scope and depth of that recall.

This draft guidance is part of a series of policy steps FDA is taking to strengthen and modernize the process for issuing a public warning about a voluntary recall and for notification of recalls, as we recently discussed in a February 26 alert. FDA Associate Commissioner for Regulatory Affairs Melinda K. Plaisier said in a press release that “there is more that needs to be done,” adding that FDA “will continue its efforts to improve recalls, and will encourage the use of new technologies and other tools that can assist in those efforts.”

The voluntary recall draft guidance is open for public comment until June 24; please contact any of the above-listed authors if you have any questions about the guidance or may be interested in commenting. We will continue to keep you apprised of new FDA efforts to inform companies on proper procedures for voluntary recalls.

]]>On February 26, FDA published the proposed rule, “Sunscreen Drug Products for Over-the-Counter Human Use,” which describes the conditions under which Over-the-Counter (OTC) sunscreen monograph products are generally recognized as safe and effective (GRASE) and not misbranded. Primarily, the proposed rule seeks additional information on sunscreen ingredients so that FDA can evaluate their GRASE status in light of changed conditions, including substantially increased sunscreen usage and exposure, and evolving information about the potential risks associated with these products. The proposal is for a final monograph on sunscreens, which would substantially amend the 1999 final rule on sunscreens that was stayed before its effective date.

Challenging Timeframe for FDA

Under the Sunscreen Innovation Act (SIA), 21 USC 360-fff-5, FDA is required by law to finalize and make effective the sunscreens final monograph by November 26, 2019. FDA is aware that time is running out on this deadline, and the agency is vulnerable to litigation if FDA fails to meet the statutory deadline. See Ctr. for Food Safety v. Hamburg, 954 F. Supp.2d 965 (N.D. Cal. 2013) (providing declaratory relief regarding statutory deadlines for rulemaking).

Having the rule become effective by November 26, 2019, will be very challenging for FDA. Under the Administrative Procedure Act, 5 USC 553(d), a rule generally cannot become effective until at least 30 days after publication, which means that FDA should publish the final rule by October 25. But the comment period on the proposed rule does not close until May 28, which gives FDA less than five months to prepare and publish the final rule. This timeframe will be very difficult for FDA for several reasons. First, this is a lengthy and complex rule that has been under development for many years. The proposed rule covers 71 (three-column) pages in the Federal Register, including multiple scientific, legal, and policy issues. FDA will need to address multiple comments and deferral requests. Second, OTC drug monograph work requires specialized knowledge, and FDA has a relatively small team dedicated to this work. Third, ordinarily, a final rule would be expected to be submitted to OMB for interagency review at least 90 days before publication, unless OMB waives review. See Executive Order 12866, Sec. 6(b)(2)(B). Adding time for the review processes at FDA and, possibly, the Department of Health and Human Services (HHS), further adds to the challenge facing the OTC drug team at FDA.

Sunscreen Ingredients and Enforcement Policy

The proposed rule states that there is still not enough evidence to determine the GRASE status of most of the ingredients from the stayed 1999 final sunscreens rule. The proposal does not address the sunscreen active ingredients that were originally submitted under FDA’s Time and Extent Application regulations, which are being addressed through the process established under the SIA. However, FDA proposes that two sunscreen ingredients are GRASE (Category I) and two are not GRASE (Category II). The ingredients proposed for Category I are zinc oxide and titanium dioxide. The ingredients proposed for Category II, based on safety concerns, are para-aminobenzoic acid (PABA) and trolamine salicylate. FDA states that neither of these ingredients is currently marketed in a sunscreen product in the U.S.

For the remaining twelve ingredients from the stayed 1999 sunscreens rule, FDA is seeking more information (Category III), based in part on concerns about the lack of data characterizing their absorption or, in the case of oxybenzone, concerns about the effect of absorption. The twelve ingredients are: cinoxate, dioxybenzone, esulizone, homosalate, meradimate, octinoxate, octisalate, octocrylene, padimate O, sulisobenzone, oxybenzone, and avobenzone. Many of these ingredients are in sunscreens that are currently marketed in the U.S. The data gaps that FDA has identified for these products are significant and are not likely to be resolved before FDA finalizes this rule as required by the statutory deadline. When FDA publishes the final sunscreen rule the agency will have two choices for each of these Category III ingredients: FDA can either (1) determine that the ingredients are not GRASE, which will require an NDA for continued marketing, or (2) defer rulemaking for these ingredients to allow the necessary research to be conducted, submitted, and evaluated.

The proposed rule states that any requests for the deferral of rulemaking must be submitted within the 90-day comment period (by May 28, 2019). Data submitted in such “timely and complete” deferral requests will be reviewed along with data and information already in the docket. “FDA will determine whether the sum of the data, if timely submitted, is likely to be adequate to provide all the data that are necessary to make a determination of general recognition of safety and effectiveness.” 84 FR 6204, 6249 (Feb. 26, 2019). This language in the proposed rule implies that even if a deferral request is submitted within the deadline, FDA may decide not to grant a deferral for certain ingredients for which FDA believes the data are unlikely to be adequate. Products containing these ingredients would need to be reformulated or come off the market.

However, FDA would extend the compliance period for one year after the effective date of the final rule, allowing products to be sold that are already delivered for introduction into interstate commerce before May 28, 2020. This would be a substantial shift from the enforcement policy that has been in place for sunscreen ingredients for more than 20 years and was revised less than a year ago for all of the ingredients in the stayed 1999 sunscreens rule. However, the May 2018 enforcement policy was clear that it “only applies until a final sunscreen monograph becomes effective.” Nonetheless, after many years of little change in the active ingredients in sunscreen products marketed in the U.S., significant change is clearly on the horizon.

What to Make of All of This?

Clearly FDA has the authority to seek additional safety data to assess the GRASE status of these sunscreen ingredients. However, companies may argue in their comments on the proposed rule that these products have a long history of use in the U.S. by millions of consumers without any significant harm, and thus have a favorable risk benefit profile. Further, they will likely assert that when weighing the dangers of skin cancers associated with sun exposure versus the absorption concerns FDA has, that the products should be considered GRASE.

Next, the twelve Category III sunscreen ingredients are used in numerous sunscreen products in the U.S. Ninety days is not a long time for companies to decide, perhaps by banding together, to evaluate available data on absorption for each of the ingredients and to seek deferrals. If deferrals are not sought and/or if FDA determines that the data are unlikely to be adequate and denies deferral requests, some or all of these ingredients may be determined to be not GRASE (Category II) in the final rule. If FDA decides not to grant deferrals for all twelve of these ingredients, the U.S. market would be cleared of chemical sunscreens, and only result in two mineral-based options. An unintended effect of this scenario may be that less consumers use sun protection products, thereby increasing unprotected sun exposure—definitely not a desirable public health outcome.

It is worth noting that the U.S. has been criticized for years as lagging behind the rest of the world in our sunscreen technology. Numerous other countries allow ingredients not considered GRASE in the U.S. on their retail shelves. The SIA was enacted, in part, to catch us up by allowing additional sunscreen active ingredients in to the drug review. FDA has evaluated several time and extent applications for additional ingredients using the process set forth in the SIA, but has found them all to have significant data gaps. Now with the looming deadline to finalize the sunscreen monograph, and the potential to find fourteen additional ingredients as non-monograph, the U.S. sunscreen market may significantly depart from the variety of skin protection availability elsewhere around the globe, which could have potentially adverse net consequences for public health.

If you have any questions about the proposed rule or may be interested in submitting a comment or deferral request, please contact any of the authors of this blog or the Hogan Lovells lawyer with whom you regularly work.

]]>Would you like an extra application with that? FDA mulls requiring dual applications for combination productshttps://www.hlregulation.com/2019/02/08/would-you-like-extra-application-fda-mulls-requiring-dual-applications-combination-products/
Fri, 08 Feb 2019 22:35:02 +0000https://www.hlregulation.com/?p=11034On Tuesday, FDA announced the availability of a draft guidance, “Principles of Premarket Pathways for Combination Products,” with high-level information on ways to bring combination products to market. Although the draft guidance doesn’t break new ground, it provides some useful clarity; for example, it includes detailed illustrations of five circumstances when those pathways apply. Citing

]]>On Tuesday, FDA announced the availability of a draft guidance, “Principles of Premarket Pathways for Combination Products,” with high-level information on ways to bring combination products to market. Although the draft guidance doesn’t break new ground, it provides some useful clarity; for example, it includes detailed illustrations of five circumstances when those pathways apply.

approval pathways available for device-led, drug-led, and biologic-led combination products, as well as considerations for making such pathway determinations

safety and effectiveness data and information sponsors must offer, depending upon the pathway

Other key issues:

The draft guidance says “a single application is generally appropriate for a combination product,” but “may not be appropriate in limited cases.” With that in mind, FDA is seeking comments about when two applications – one to the lead jurisdictional agency Center and one to the non-lead Center – should be submitted.

FDA’s Office of Combination Products (OCP) directs the Centers to coordinate on combination product approval requests, “including by ensuring that Agency components and staff coordinate appropriately on premarket review of these products, and that Agency thinking is aligned in conducting these reviews.” This may suggest an internal FDA view that the Centers have not been fully aligned in reviewing submissions, and perhaps it signals greater OCP involvement, both to encourage robust involvement across the agency and to mediate any resulting conflicts.

FDA expressly addresses an issue that may have been imperfectly understood and inconsistently applied, stating that “the data and information needed to address safety and effectiveness questions related to the non-lead constituent part of a combination product may differ from the data and information needed to obtain marketing authorization for that article as a stand-alone product that is not part of a combination product.”

Generally, the draft guidance is consistent with the existing practice regarding Center jurisdiction and pathway processes for combination products, and doesn’t add much in the way of substance. In the examples annex, for instance, FDA reiterates the existing approach to when a 510(k) is not an available pathway to market, but the agency does not suggest a mechanism for determining the appropriate pathway in those circumstances, leaving significant leeway for FDA discretion.

In a press release announcing the guidance, Commissioner Gottlieb touted the potential benefits of combination products, saying the draft guidance aims to “enhance clarity, predictability, efficiency and consistency of premarket review for combination products.” The draft guidance is intended to comply with the 21st Century Cures Act’s mandate of greater transparency in combination product designations. Earlier efforts toward this end include the September 2017 final guidance on the agency’s classification process for distinguishing between a drug, device, biologic, and combination product, which we analyzed here. FDA also issued a proposed rule in May 2018 related to streamlining combination product regulations, but it was generally limited in scope.

FDA will accept comments on the new draft guidance until May 29. If you have questions about this guidance or may be interested in submitting a comment, please contact any of the authors of this blog or the Hogan Lovells lawyer with whom you regularly work.

]]>FDA Commissioner Scott Gottlieb, M.D. recently announced four steps FDA will be taking to ensure that the Orange Book (FDA’s publication of Approved Drug Products with Therapeutic Equivalence Evaluations) provides the greatest benefit to patients and providers, and (perhaps in particular) generic drug developers. The Commissioner’s announcement addresses several important issues, including patent listing standards and therapeutic equivalence ratings.

Dr. Gottlieb said that in the coming year, FDA will issue draft guidance describing how the FDA evaluates therapeutic equivalence (TE) and assigns TE codes, which are published in the Orange Book. An “A” rating indicates that products are therapeutically equivalent and signals to pharmacists and others that FDA considers the products to be substitutable for one another. To be “A” rated, products must contain the same active ingredient, with the same dosage form, route of administration and strength, and they must be bioequivalent to each other. These criteria are largely synonymous with the requirements for approval of generic drugs under 505(j). Thus, drugs approved under ANDAs are assigned “A” ratings, indicating that they may be substituted for the branded pioneer product.

The agency, however, seems particularly interested in TE ratings for complex drug products, and the potential to assign TE ratings to products under 505(b)(2) NDAs. Dr. Gottlieb said:

We believe this will be particularly beneficial for those seeking to develop generic products for harder-to-copy complex drugs that often face greater scientific and regulatory challenges and thus often have less competition. For some of these drugs, the 505(b)(2) pathway may provide a more efficient development path and the agency is developing policy for how manufacturers can acquire a therapeutic equivalence rating to allow for full substitutability for products developed by this route.

Unlike drugs approved under ANDAs, drugs approved under 505(b)(2) need not be “the same” as the pioneer product, and FDA has less latitude to assign them “A” ratings. FDA’s initiative seeks to maximize this latitude.

Second, Dr. Gottlieb stated that FDA will be soliciting public comment on Orange Book use and potential enhancements, including a re-examination of the types of pharmaceutical patents that must be listed in the Orange Book. Listing patents in the Orange Book that claim the approved drug or method of using the drug is a key part of the Hatch-Waxman balancing of interests between pioneer and generic drug sponsors, affecting procedural protections and incentives for both sides. Dr. Gottlieb indicated that FDA plans to consider novel issues associated with new technologies, such as whether an application holder for a drug product that has been approved for use in conjunction with a digital application should be required to list any patents associated with that app. This will be a key issue in a rapidly emerging area of pharmaceutical product development.

FDA also may address other patent listing issues previously raised by stakeholders. For example, FDA may seek to clarify the line between patents directed to “packaging” for a drug product, which are not generally listable, and patents directed to containers, closures, and other delivery-system components considered integral to the “dosage form” of the drug product (e.g., transdermal patches, metered dose inhalers, and pre-loaded syringes), which generally are listable.

Additionally, Dr. Gottlieb announced a new draft guidance titled “Marketing Status Notifications Under Section 506I of the Federal Food, Drug, and Cosmetic Act; Content and Format,” which is intended to provide approved drug application holders with clarity on the specific categories and descriptions of the information that they are required to share with FDA on the marketing status for their brand and generic drugs, as well as clarity on how to provide that information in a timely and consistent manner.

Section 506I was enacted in 2017 and requires NDA and ANDA holders alike to provide written notice to FDA within 180 days of approval if the drug will not be available for sale by that time. It also requires 180 days written notice prior to withdrawing a drug product from sale. Previously, the process for informing FDA that an approved product has been discontinued or withheld from sale was governed informally and there was no “advance warning” system, except in limited circumstances . As Dr. Gottlieb notes, FDA’s intent is to provide transparency around circumstances where generic competition is lacking.

Last, Dr. Gottlieb announced plans to issue a draft guidance to provide answers to questions frequently asked by drug product applicants and approved application holders in using the Orange Book. Overall, the Commissioner emphasized FDA’s goal to “allow generic competitors to better assess which products they choose to develop and provide greater clarity as to the path to market, [and] to make generic drug development more efficient and predictable.”

Comments will be accepted on the Marketing Status Notifications draft guidance until April 1, and there will be opportunities to comment on the forthcoming related draft guidances as well. With much at stake, generic and pioneer drug manufacturers alike should be following these developments closely and seeking to comment.

]]>Likely FDA Impact of the Government Shutdown: Regulatory Submission Reviews, Inspections, and Research Projectshttps://www.hlregulation.com/2018/12/27/fda-impact-government-shutdown-regulatory-submission-reviews-inspections/
Thu, 27 Dec 2018 23:26:12 +0000https://www.hlregulation.com/?p=10952The U.S. government shutdown that began December 22, 2018 affected only about a quarter of federal agencies, because most had already been funded for FY 2019. Unfortunately, FDA is one of the agencies with at least some functions shut down, as was announced yesterday. Among other things, FDA has furloughed 42% of its employees, according

]]>The U.S. government shutdown that began December 22, 2018 affected only about a quarter of federal agencies, because most had already been funded for FY 2019. Unfortunately, FDA is one of the agencies with at least some functions shut down, as was announced yesterday. Among other things, FDA has furloughed 42% of its employees, according to a tweet from Commissioner Scott Gottlieb, M.D. Nonetheless, Dr. Gottlieb said the agency would be “continuing vital activities, to the extent permitted by the law, that are critical to ensuring public health and safety in the United States,” including:

Maintaining core functions to handle and respond to emergencies,

Supporting high-risk food and medical product recalls,

Pursuing civil and criminal investigations when the public health may be imminently at risk,

Screening imported food and medical products,

Addressing other critical public health issues that involve imminent threats to the safety of human life, and

On the other hand, until legislation making FY 2019 appropriations for FDA is enacted, the agency will not be able to:

Accept user fees assessed for FY 2019, or

Accept any regulatory submissions for FY 2019 that require a user fee payment and that are submitted during the lapse period.

According to an HHS contingency staffing plan, FDA will “be unable to support some routine regulatory and compliance activities,” including “some medical product, animal drug, and most food related activities.” The plan says FDA “will also pause routine establishment inspections, cosmetics and nutrition work, and many ongoing research activities.”

Possible Implications for CDER-Regulated Products

The impact on CDER will be similar to the other product Centers that rely on user fees. The biggest impediment will be that FDA will not accept new applications or supplements that require a fee because fees cannot be processed during the lapse period. Otherwise, the user fee-supported activities will generally continue. For PDUFA, that includes the broadly defined “process for the review of human drug applications,” under Sec. 735(6) of the Act, which includes the “activities necessary for the review of human drug applications and supplements.” But based on past experience with FDA shutdowns, the absence of a significant portion of the FDA staff, over time, places a strain on CDER drug review activities, which can cause delays that indirectly affect drug review.

Implications for CDRH-Regulated Products

It will not accept any applications subject to user fees if the user fee has not been paid and fully processed prior to the lapse in funding.

It will accept such filings for review if the user fee was paid and fully processed prior to the funding lapse.

If the user fee has been paid but not fully processed prior to the funding lapse, the application will be placed on user fee hold until the government reopens and the payment can be fully processed.

Additionally, Hogan Lovells has learned through direct agency discussions that processing of Investigational Device Exemptions is expected to continue.

Some agency correspondence is likely to be delayed, particularly for informal inquiries or those not subject to user fees. For example, the Office of Combination Products has communicated that it is not able to read or respond to messages until either a FY 2019 appropriation or continuing resolution for FDA has been enacted. Similar communication delays are anticipated among other FDA offices.

In sum, while FDA’s review of pending applications subject to user fees is expected to continue during this partial shutdown, new applications subject to user fees will not be reviewed until such time as a FY 2019 appropriation or continuing resolution for the FDA is enacted and the fee processing office reopens. Depending on the length of the shutdown, medical product centers may well be looking at a sizable backlog of applications to triage when the agency is fully operational again, not to mention other industry correspondence. Thus, if the current shutdown persists, industry should anticipate that certain agency delays will likely continue for some time.

With respect to domestic and foreign inspections, it is unclear to what extent the furlough period will impact scheduling of these inspections into 2019.

In a Thursday letter to FDA employees, Dr. Gottlieb expressed sympathy for the challenges that the shutdown would impose on agency staff. We will continue to monitor and report on how the government shutdown is affecting regulatory work in the U.S.

]]>FDA Finalizes Data Integrity Guidance, With Some Noteworthy Changeshttps://www.hlregulation.com/2018/12/12/fda-finalizes-data-integrity-guidance-noteworthy-changes/
Wed, 12 Dec 2018 23:11:15 +0000https://www.hlregulation.com/?p=10911Earlier today, FDA published its finalized Data Integrity Guidance. The Final Guidance is entitled “Data Integrity and Compliance With Drug CGMP: Questions and Answers,” and updates the agency’s April 2016 Draft Guidance covering the design, operation, and monitoring of systems and controls to maintain data integrity to comply with current good manufacturing practice (cGMP) for

]]>Earlier today, FDA published its finalized Data Integrity Guidance. The Final Guidance is entitled “Data Integrity and Compliance With Drug CGMP: Questions and Answers,” and updates the agency’s April 2016 Draft Guidance covering the design, operation, and monitoring of systems and controls to maintain data integrity to comply with current good manufacturing practice (cGMP) for drugs. The Final Guidance says that in recent years, FDA has “increasingly observed cGMP violations involving data integrity” during inspections, and in a statement announcing the guidance, FDA Commissioner Scott Gottlieb, M.D. similarly expressed concern over data integrity violations that have been the result of both deceptive practices and inadequate controls and oversight to ensure reliable and accurate data.

Although the Final Guidance largely aligns with the Draft Guidance, there are some notable differences. In particular:

An expansive interpretation of FDA’s inspectional authority under 21 USC 374 and lack of clarity on how it applies to foreign establishments. In Footnote 14 in the Final Guidance, FDA indicates that pursuant to 21 USC § 374(a), the agency may inspect “records not intended to satisfy a CGMP requirement but which nonetheless contain CGMP information.” FDA also states on page 12 of the Final Guidance that “an email to authorize batch release is a CGMP record that FDA may review” pursuant to its 21 USC § 374(a) inspectional authority. This interpretation of 21 USC § 374 is noteworthy because it could be read to go beyond what FDA generally has authority to inspect, for example, email containing personnel information that could cover a broad range of information. Under 21 USC § 374, FDA only has the statutory authority to inspect personnel records that go to the qualification of technical and professional personnel. Similarly, FDA’s authority to inspect records does not extend to financial data, sales data (other than shipment data), pricing data, and research data (other than data relating to 21 USC § 355(i) (investigational new drug), § 355(k) (postmarket studies), or § 355(j) (abbreviated new drug applications)). It also raises the question as to how FDA would go about locating emails containing CGMP information (that are not technically CGMP records) without reviewing significant amounts of email records that very well could be outside the scope of 21 USC § 374.

Additionally, while relying on 21 USC § 374, the Final Guidance does not differentiate between foreign and domestic inspections with regard to this potentially expansive interpretation and how it will be applied outside the United States. This is noteworthy because much of FDA’s data integrity enforcement has focused on manufacturing sites outside the United States and FDA has itself recognized that its access to foreign establishments and the records therein does not come from FDA’s inspection authority under 21 USC § 374.[1] This is why, for example, FDA investigators do not issue a Form FDA 482, Notice of Inspection, when conducting a foreign inspection. For an inspection under 21 USC § 374, FDA investigators are required to issue a Form FDA 482 to each firm inspected.[2] But FDA investigators are instructed not to issue a Form FDA 482 during foreign inspections, as 21 USC § 374 does not apply during foreign inspections.[3] FDA’s ability to conduct foreign inspections has historically derived from the fact that if an inspection or a request to review records is refused, FDA can take measures to deny access to the United States market (via import refusal and withholding of application approvals).

Increased emphasis on the critical role of senior management in creating a quality culture that identifies and addresses data integrity risks. For example, the preamble to the Final Guidance states that “[m]anagement’s involvement in and influence on” strategies to identify and address data integrity risk is “essential in preventing and correcting conditions that can lead to data integrity problems.” The Final Guidance also states that “[i]t is the role of management with executive responsibility to create a quality culture where employees understand that data integrity is an organizational core value and employees are encouraged to identify and promptly report data integrity issues. In the absence of management support of a quality culture, quality systems can break down and lead to CGMP noncompliance.” This could signal an increased willingness on the part of FDA to hold senior management, including corporate management, responsible for data integrity issues identified at manufacturing sites.

Clarifying that invalidated data must be evaluated by the quality unit pursuant to release. While the Draft Guidance was silent on the issue of whether legitimately invalidated data should be included within the scope of the quality unit’s batch record review pursuant to release, the Final Guidance expressly addresses this point: “Even if test results are legitimately invalidated on the basis of a scientifically sound investigation, the full CGMP batch record provided to the quality unit would include the original (invalidated) data, along with the investigation report that justifies invalidating the result.” This difference is consistent with how we have seen FDA enforce the Draft Guidance in the field with respect to invalidated data.

More stringent requirements regarding access controls. Whereas the Draft Guidance recognized that some manufacturers may be too small to support independent security role assignments — e.g., for system administrators — the Final Guidance does not include this provision. The Final Guidance simply states that the “system administrator role, including any rights to alter files and settings, should be assigned to personnel independent from those responsible for the record content.” The Final Guidance further states that manufacturers should “establish and implement a method for documenting authorized personnel’s access privileges for each CGMP computer system in use (e.g., by maintaining a list of authorized individuals).” Regarding shared accounts, the Final Guidance states that even read-only shared accounts are not permissible.

Enhanced requirements relating to audit trail review. Whereas the Draft Guidance recommended that “audit trails that capture changes to critical data be reviewed with each record and before final approval of the record,” (emphasis added) the Final Guidance states that “[i]f the review frequency for the data is specified in CGMP regulations, adhere to that frequency for the audit trail review.” The Final Guidance further clarifies that audit trails should be reviewed “after each significant step in the manufacture, processing, packing, or holding” of a drug, and before batch release. This difference between the Draft Guidance and Final Guidance is potentially significant in that it could increase the amount of data reviewed during manufacturing and batch release. The Final Guidance does not clarify the scope of audit trail review —i.e., what time points should be included within the scope of the quality unit’s review, particularly at batch release.

Overall, the Final Guidance shows that data integrity remains a top enforcement priority for FDA, and the agency will expect manufacturers to be in compliance with the expectations detailed in the Final Guidance moving forward.

If you have questions regarding the Final Guidance and FDA’s application of the requirements therein—or data integrity more generally—please contact Jim Johnson or Chris Fanelli, or a Hogan Lovells lawyer you regularly work with.

[1] “[T]he authority to inspect foreign drug facilities does not come from [21 USC § 374] of the Food, Drug and Cosmetic Act (the Act), but from the agency’s ability to exercise [21 USC § 381] of the Act and commitments made by the sponsors of applications, if applicable.” FDA’s Guide To Inspections of Foreign Pharmaceutical Manufacturers, available at https://www.fda.gov/iceci/inspections/inspectionguides/ucm075021.htm.

]]>With the opportunity for global pharmaceutical companies to gain new access to the Chinese market presenting itself like never before (see our previous blog posts here and here), significant news broke on December 7, 2018, regarding a newly implemented pilot centralized drug procurement program (the “program”) that will have significant ramifications for global pharmaceutical companies. Specifically, China just announced the reduction of prices for certain off-patent generic drugs by up to 96%. Under the program, the government will award a contract to the lowest bidder, who will be guaranteed a sale volume of 60-70% of the total market for a year. The move is aimed at reducing drug prices and encouraging consolidation in the generic drug industry. The program will be a significant change in how generic drugs are priced and procured in China.

The framework of the program was established by the Central Comprehensively Deepening Reforms Commission (CCDRC), a governing agency that is directly lead by the Politburo of the Communist Party of China. The CCDRC has entrusted the Shanghai City Government to implement the program, which covers 11 major cities in China, including Beijing, Tianjin, Shanghai, Chongqing, Shenyang, Dalian, Xiamen, Guangzhou, Shenzhen, Chengdu, and Xi’an. Together, according to a Chinese news source (“21st Century Business Herald”), the combined healthcare markets from these 11 cities constitute about 30% of the total Chinese market. Under the program, pharmaceutical companies had the opportunity to submit bids for 31 generic drugs and the contracts were awarded under the following principles:

When there are three or more bidders, the lowest bidder will automatically be awarded the contract.

When there are two bidders, the lower bidder will be chosen to further negotiate with the procurement office. The drug price discount rate will be negotiated using the average discount rates from other generic drugs as a reference.

When there is just one bidder, the drug price discount rate will be negotiated using the average discount rates from other generic drugs as a reference.

After the bidding, which took place on-site in Shanghai, generic drug manufacturers were awarded contracts for 25 generic drugs with guaranteed sale volume in the 11 major cities in China. The average price dropped 52%, with the highest price reduction being 96%. We have translated the drugs that were awarded contracts under the program in a list below. While many global pharmaceutical companies participated in the bidding process, all but two successful bids came from domestic Chinese drug manufacturers. Additional information on the generic drug manufacturers who had winning bids and the pricing information can be found online at: http://www.smpaa.cn/gjsdcg/files/file5772.pdf.

No.

Drug

Drug Manufacturer

1

Atorvastatin calcium tablets

Beijing Jialin Pharmaceutical

2

Rosuvastatin calcium tablets

Zhejiang Jingxin Pharmaceutical Co. Ltd.

3

Clopidogrel hydrogen sulfate tablets

Shenzhen Salubris Pharmaceuticals

4

Irbesartan tablets

Zhejiang Huahai Pharmaceutical Co., Ltd.

5

Amlodipine besylate tablets

Zhejiang Jingxin Pharmaceutical Co. Ltd.

6

Entecavir dispersible tablets

Chia Tai Tianqing Pharmaceutical Group Co. Ltd

7

Escitalopram oxalate tablets

Kelun Group

8

Paroxetine hydrochloride tablets

Zhejiang Huahai Pharmaceutical Co., Ltd.

9

Olanzapine tablets

Jiangsu Hansoh Pharma

10

Cefuroxime axetil tablets

Chengdu Brilliant Pharmaceutical Co., Ltd

11

Risperidone tablets

Zhejiang Huahai Pharmaceutical Co., Ltd.

12

Gefitinib tablets

AstraZeneca AB (Kagamiishi Plant, Nipro Pharma Corporation)

13

Fusinopril tablets

Sino-American Shanghai Squibb Pharmaceuticals Co., Ltd.

14

Irbesartan hydrochlorothiazide tablets

Zhejiang Huahai Pharmaceutical Co., Ltd.

15

Lisinopril tablets

Zhejiang Huahai Pharmaceutical Co., Ltd.

16

Tenofovir disoproxil fumarate tablets

Chengdu Brilliant Pharmaceutical Co., Ltd

17

Losartan potassium tablets

Zhejiang Huahai Pharmaceutical Co., Ltd.

18

Enalapril maleate tablets

Yangtze River Pharmaceutical Group

19

Levetiracetam tablets

Zhejiang Jingxin Pharmaceutical Co. Ltd.

20

Imatinib mesylate tablets

Jiangsu Hansoh Pharma

21

Montelukast sodium tablets

Anbisheng System

22

Montmorillonite powder

Simcere Pharmaceutical Group

23

Pemetrexed disodium for injection

Sichuan Huiyu Pharmaceutical

24

Flurbiprofen axetil injection

Sichuan Huiyu Pharmaceutical

25

Dexmedetomidine hydrochloride injection

Yangtze River Pharmaceutical Group

It is unclear when this program will be rolled out nationwide and how many generic drugs will eventually be covered. It is important to recognize that under the program, the only determining factor for a successful bid will be the price. Thus, as global pharmaceutical companies look to do business in China, the implementation of this program will undoubtedly impact strategies on how to commercialize drug products in China and how to best compete in a bidding war with a domestic Chinese drug manufacturer.

It is also notable that this program has caused significant impact in the Chinese financial markets. Stocks have reacted negatively thus far. It will be interesting to see whether the concept of “lowest bid wins” affects the public’s view of the quality of their drug products. On the other hand, it is expected the program will facilitate the generic drug industry’s consolidation and push more Chinese pharmaceutical companies towards innovative drug research and development. We will be monitoring the program closely, and particularly looking at whether there are any changes made to the program once rolled out nationwide.